The word may still be out on whether certain oral diabetes medications puts patients at risk for lower limb complications, but a new study has shown that liraglutide is not one of them. A post hoc review analysis of the LEADER trial published in Diabetes Care examined the effects of Liraglutide on rates of foot ulceration and amputation in patients at high risk for cardiovascular (CV) events.

Liraglutide, a GLP-1 agonist, is an injectable glucose-lowering medication used in patients with type 2 diabetes. GLP-1 agonists act by mimicking the effects of the hormone GLP-1, which increases insulin secretion and lowers glucagon release. This, in effect, causes increased satiety and slowed gastric emptying, with one of the main benefits of GLP-1 agonists being weight loss in patients with diabetes.

Researchers in the present study pulled data from the LEADER trial (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results), a randomized double-blind controlled trial during which patients with type 2 diabetes and risk for CV events were assigned to either liraglutide or placebo groups. The treatment group received 1.8mg/day of liraglutide and was compared to a controlled placebo group.

During analysis, patients were classified as having a diabetic foot ulcer (DFU) if they reported a new onset DFU or worsening of an existing DFU. Amputation was categorized as minor (midtarsal or distal amputation), major (any resection proximal to the midtarsal level), or unknown (could not be classified as minor or major based on available data).

A total of 4,668 participants were randomized into the liraglutide group and 4,672 participants into the placebo group. Participants were followed for a median duration of 3.8 years. Hazard ratios were calculated using Cox regression model and incidence of events was estimated using the Aalen-Johansen method.

Overall, there were 260 DFU events that occurred in 176 patients in the liraglutide group, and 291 events that occurred in 191 patients in the placebo group. When examining the time to first DFU event and mean number of DFUs, although both were slightly less in the liraglutide group compared to placebo, no significant difference was found (p=0.41, p=0.76, respectively).

When examining DFU-related amputations, however, investigators found that patients treated with liraglutide had a significantly lower number of amputations compared to the placebo group. Cox regression analysis showed a statistically significant risk reduction in amputations with liraglutide (p = 0.028).

Based on results from the post hoc analysis, it was shown that patients with type 2 diabetes and a high risk of CV events were at no greater risk for developing DFUs compared to patients taking placebo. Investigators did note, however, that patients taking liraglutide were at a significantly lower risk for amputations relating to DFUs than patients on placebo.

With growing concern over diabetes-related complications, this knowledge provides tremendous opportunity for GLP-1 agonists to play a larger role in specific patient populations. Foot ulcers and other lower limb complications are a significant burden on the diabetes community. Further investigation of the claims made in this study are necessary, but provide compelling evidence for future research.

Practice Pearls:

Treatment with liraglutide was not associated with an increased risk of developing or worsening diabetic foot ulcers compared with placebo in patients with type 2 diabetes and risk for CV events.

In 2015, the American Diabetes Association reported that almost 10% (30.3 million adults) of the United States population was afflicted with diabetes mellitus and another

84.1 million adults had prediabetes. This staggering number continues to grow and has proven to be a tremendous burden on the healthcare system. With an estimated 1.5 million Americans diagnosed with diabetes each year programs designed to help reduce the number of adverse events are instrumental in preventing morbidity and mortality. While it is well known that the most common complications of diabetes include neuropathy, retinopathy, nephropathy, cardiovascular disease and skin disorders there have been few studies evaluating the risk of falls in this population.

Upwards of 70% of patients with diabetes experience peripheral neuropathy. Patients with peripheral neuropathy are at an increased risk of falls, fractures and contusions due to impaired proprioception and unsteady gait. Additionally, diabetic foot ulcers (DFU), another cause of concern for patients, also increase a patient’s chances of falling. In a previous prospective study that examined patients with a history of DFU reported that 63% of their 400-participant population had fallen over a 2-year follow-up period.

A retrospective study examining all VHA hospitalized patients determined that more than half of patients had a diagnosis of diabetes mellitus, and lower extremity ulcers and amputations accounted for more than one-half of hospitalizations. On average, veterans are at least 2 times more likely to be afflicted by diabetes. Researchers at the James A. Haley Veteran’s Administration Hospital in Tampa, Florida aimed to investigate the prevalence of DFU and the rate of adverse events such as amputations, falls, fractures and infection. Using the ICD-9 codes for DFU, lower extremity amputations, falls, fracture and infection all patient records were scanned for the aforementioned criteria. From there, researchers analyzed if the conditions were related to diabetes and if so, were included in the sample size. There were 3,586 individuals diagnosed with DFU and 40,938 individuals with diabetes and without DFU. Comorbidities were more prevalent among individuals with DFU than without.

A diagnosis of peripheral vascular disease was most common (39.5%) in patients with DFU followed by peripheral neuropathy (23.2%). A statistically significant difference was noted between the DFU and non-DFU groups with respect to the prevalence of PVD and peripheral neuropathy (P <0.0000001) The most common adverse events among patients with DFU were infection (39.5%), amputation (16%) and falls (14.6%). While an increased risk of infection and amputation is expected in patients with DFU the number of participants that had reported falls was much higher in the DFU group than in the non-DFU group.

This study shows that participants with diabetes and history of DFU were at an increased risk of infection, amputation, falls and fractures in comparison to the non-DFU group. It was also noted that patients with DFU were statistically significantly more likely to have a diagnosis of peripheral vascular disease and peripheral neuropathy. However, there are some limitations to this study and the results reported. First, it was not noted whether patients were diagnosed with DFU before or after a diagnosis of peripheral vascular disease or peripheral neuropathy. While it can be assumed that the DFU was due to these two complications it was not explicitly stated which occurred first. Second, it was reported that patients with DFU were more likely to experience the adverse events previously stated, however, more patient characteristics such as paralysis, prior limb loss unrelated to diabetes, morbid obesity and advanced age were not disclosed as possible reasons for the falls and fractures. It should also be noted that while there was an increase in comorbidities in the diabetes with DFU group, there was still incidence of falls and fractures in the non-DFU group, albeit it was less likely.

Further research is still warranted regarding the risk of falls and fractures in patients with diabetes who have DFU. For now, healthcare providers can educate patients on ways to mitigate the risk of experiencing these adverse events in diabetes populations with foot ulcers.

Practice Pearls:

Patients with diabetic foot ulcers were more likely to suffer from peripheral neuropathy and peripheral vascular disease in comparison to patients without DFUs

Amputations can be a major potential complication of diabetes. Only a small percentage of people diagnosed with diabetes require amputations, diabetic patients still account for approximately 60% of non-traumatic lower-limb amputations performed in people over the age of 20. Since diabetes is a major risk factor for peripheral arterial disease (PAD), it is important to properly manage PAD in order to reduce complications down the rode in diabetes patients. Although statins are recommended for PAD patients, there is little research as to whether statins are an effective option to aid the prevention of amputations in type 2 diabetes patients.

Researchers used data from Taiwan’s National Health Insurance Research Database (NHIRD) to “investigate whether the use of statins is associated with a lower extremity amputation rate in a high risk population with known PAD as compared to two propensity score-matched cohorts without statin use while taking into consideration the competing risk of death.” The study population included patients who were age 20 or older with a diagnosis of both diabetes mellitus and peripheral arterial disease during the search period and had 5 years of data before inclusion in the study. Patients were then divided into three groups based on current PAD treatment: statin-user, non-statin lipid-lowering agent, or non-user. Patients who were excluded from the study were those who were on a combination of statins and other lipid-lowering agents. A propensity score was calculated for patients to determine the probability of a patient receiving a lipid-lowering agent and control patients were matched to both statin and non-statin users with a similar propensity. The primary outcome of the study was new lower extremity amputation and secondary outcomes were in-hospital cardiovascular death and all-cause mortality.

The study included a total of 69,332 diabetes patients with a mean age of 62.6 years who were diagnosed with PAD during the study period. The majority of the patients, approximately 77%, were non-users of lipid-lowering agents, 17% of the patients were statin users, and 6% used non-statin lipid-lowering agents. Over approximately 5.7 years of follow up, patients in the statin user group had less incidence of any lower extremity amputation, less total lower extremity amputation, and less in-hospital cardiovascular death and all-cause mortality compared to non-users. After adjusting for relevant factors, statin users had significantly lower risk of lower extremity amputation events (adjusted HR [aHR] 0.75, 95% CI 0.62-0.90) and significantly lower risk of total lower extremity amputations (aHR 0.58, 95% CU 0.36-0.93) when compared to non-users. In comparison, non-statin lipid-lowering agents were not associated with any significant decrease in lower extremity amputation events (aHR 0.95, 95% CI 0.73-1.23) and both the statin user group and non-statin lipid-lowering agent group. For the propensity score-matched analysis, 11,373 patients from both the statin user group and non-user group were matched and 4,428 patients from both the non-statin lipid-lowering agent group and the non-user group were matched. In the propensity score-match analysis, the statin user group had a 25% lower risk of any lower extremity amputation (HR 0.75, 95% CI 0.60-0.94), 52% lower total extremity amputation (HR 0.48, 95% CI 0.28-0.83), lower in-hospital cardiovascular death (HR 0.75, 95% CI 0.66-0.87), and lower all-cause mortality (HR 0.72, 95% CI 0.67-0.77) when compared to matched non-users, while non-statin lipid-lowering agents had a neutral effect on all outcomes compared to matched non-users. Other factors, such as gender, age> 65, hypertension, heart failure, CAD, use of antiplatelet drugs, and use of a high potency statin showed no significant effects on the outcome of the study.

Statins have known pleiotropic effects that aid in its protective effects for lowering risk of amputations in diabetes mellitus patients. While this study had a very large sample size, further studies may be needed in varying populations to determine relative effect and real world practice application.

According to the ADA, treatment of diabetic foot ulcers (DFUs) along with associated infections, below the knee amputations, and surgeries to revascularize the lower limbs account for a significant portion of the costs incurred in the treatment of diabetes. Yet with the frequency of occurrence of these complications, there are very few studies that drive the paradigm toward either primary prevention (avoiding DFUs entirely) or secondary/tertiary measures (efficient treatment of DFUs in those who are not aware [secondary]/are aware [tertiary] of diabetic ulcers), which are combined into a single term (secondary prevention) for purposes of the article. Sadly, utilization of primary prevention of these complications is spotty in most health care systems, and implementation of secondary prevention is often delayed in patients with DFUs. It is speculated that one reason little attention is paid to these secondary measures may be the concern over a “small return on the investment” in trying to prevent amputations, an attitude that certainly appears to be both counter-intuitive and counterproductive. An attempt to show otherwise was made by N.R. Barshes et al. who utilized a Markov model demonstrating the probability of significant cost savings attributable to otherwise less costly preventive measures.

The idea of the Markov model allows prediction of transition from one condition to another, with the understanding that the probability of any transition is only dependent on the current condition, but not any past condition, and that these conditions exist over a continuum. A simple example would be the states of untreated, treated, and final outcomes (cure, amputation, or death, the latter two of which would be considered “inescapable” outcomes, where return to the state immediately prior is not possible). Barshes looked at 1,000 repeated simulations of 100,000 hypothetical diabetes patients with no current or historical DFU, over a period of five years in 1-month intervals. Each month, each “patient” would exist in one of six clinical states: no DFU, uninfected DFU, infected DFU, limb loss, healed DFU, and all-cause death. Based on available clinical data, the patients were stratified into low, moderate, and high risk, and transition probabilities for moving from state to state each month were assigned (for example, the chance of transitioning from no DFU to initial DFU event in moderate risk patients was 0.3%, while the chance of limb loss in undertreated DFU in high risk was 3.1%). Each of the simulations was run with transitions occurring over five years (60 months/transitions), and the outcome probabilities were pooled. Each outcome was assigned a monthly cost estimate (for example, the median monthly cost of a healed DFU was $45, infected DFU $12,955, and major limb amputation such as BKA $38,934). Remember, each of these costs were per case, not the total population.

By applying costs of both primary and secondary preventive measures to all levels of risk-presenting patients (low to high), cost thresholds, at which at least 90% of simulations demonstrated savings, were established. An example was a measure that decreased the occurrence of DFU by 10% (0.90 RR), costing $50 per person and would have greater than a 90% probability of reducing amputations (at almost $39K) in diabetes patients at a cost that is equal or even lower than the standard of care, compared to no preventive care. The same 10% reduction in moderate- to high-risk patients from preventive care costs $125 per patient, with increases in cost as risk reduction also increases, yet said costs are considerably less than the outcome of amputation. For the purpose of this discussion, these results have been simplified.

The lack of programs designed to prevent/eliminate DFUs is troubling, this in spite of the known impact these DFUs have on amputation requirements, increasing healthcare costs, and overall quality of life. The paucity of such programs, even in larger academic healthcare centers, may be related to the perception of a clear lack of economic benefit. Studies have been few and far between, and prior Markov models have not demonstrated a potential for overall savings, where cost effectiveness has been shown. The difference in this study from past offerings is this one looked at differing degrees of effectiveness (risk reductions ranging from 5% to 25%), assigning costs to each and determining a likely cost threshold for determining the need for preventive measures. One important limitation stated by the authors was separating low-risk from moderate- to high-risk patients, which may cause those higher risk populations to lose favor due to increased costs of prevention. An examination of the overall population as a whole would have been warranted to help support better utilization of prevention of diabetic foot ulcers and subsequent complications. If little else, there is certainly a need to encourage preventive programs as a means to reduce these high costs of care.

Practice Pearls:

Resistance to diabetic foot ulcer prevention programs seems driven by the lack of perceived “return on investment” of such measures.

Markov models can be used to demonstrate reduction in risk of developing costly complications from DFUs

A clear cost benefit can also be demonstrated, where utilizing relatively low cost prevention can result in avoidance of significantly costlier events.

I am a diabetes educator and certified foot care nurse. Through the years, I’ve learned that most topics we teach people who have diabetes are really topics every person should know about. I teach patients how to care for their feet, how to prevent foot problems, and how to treat them if they should have problems.

I am a diabetes educator and certified foot care nurse. Through the years, I’ve learned that most topics we teach people who have diabetes are really topics every person should know about.

I teach patients how to care for their feet, how to prevent foot problems, and how to treat them if they should have problems.

I have had so many patients return from vacation with foot wounds due to the particular shoes they were wearing. Some didn’t bring enough shoes or bought and wore brand new shoes, while some wore the type of shoes we don’t recommend and some didn’t wear shoes at all.

As I write this, I am on vacation. Before leaving, I thought about the above. I needed new shoes for the trip, so I bought 2 pair of the same shoes, one normal width and one wide. I didn’t have much time before leaving, but I did practice wearing them before leaving. “Something” told me to also bring a pair of old faithfuls…shoes I have worn a lot and had no problem with.

I’m so glad I heeded my own teaching. The first day, in one of the new pair of shoes, it went pretty well, no pain or redness. After wearing them all daytime, I changed to old faithful that evening. The next morning I noted a little redness and soreness on an area of my foot. I took no chances. I wore the pair with the wide width that day. No problems.

I thought about the wisdom we teach our patients. Glad to have feeling and sight to prevent a problem I’m sure would have occurred…more personal ammunition to teach my patients.

Lessons Learned:

When helping your patients prepare for travel, always teach to take more than one pair of shoes. If they are taking new shoes, this is especially important. And…always take a pair of “old faithfuls.”

Whether traveling or not, teach your patients to “listen” to any sign of redness, soreness, or pain that is telling them to wear different shoes.

Always teach the importance of looking at feet at least daily for changes and treat them early.

Remember, what’s good for people who have diabetes is most likely good for everyone.

Heed your own knowledge and practice what you teach.

Joy Pape, FNP-C, CDE, CFCN, FAADE Associate Editor, DiabetesInControl

Anonymous

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